P-values for group sequential testing

Group sequential testing procedures are widely employed in long-termclinical trials. We discuss several methods for computing theP-value following a group sequential trial based on differentoutcome-space orderings. We use a criterion defined in thispaper to compare these methods and point out interesting differences.     

Symmetric group sequential test designs

In Phase III clinical trials, ethical considerations often demand interim analyses in order that the better treatment be made available to all patients as soon as possible. Group sequential test designs that do not treat the hypotheses symmetrically may not fully address this concern since early termination of the study may be easier under one of the hypotheses. We present a one-parameter family of symmetric one-sided group sequential designs that are nearly fully efficient in terms of the average sample number. The symmetric tests are then extended to a two-sided hypothesis test. These symmetric two-sided group sequential tests are found to have improved overall efficiency when compared to the tests proposed by Pocock (1977, Biometrika 64, 191-199) and O'Brien and Fleming (1979, Biometrics 35, 549-556). Tables of critical values for both one-sided and two-sided symmetric designs are provided, thus allowing easy determination of sample sizes and stopping boundaries for a group sequential test. Approximate tests based on these designs are proposed for use when the number and timing of analyses are random.     

Tyrosine specific sequential labeling of proteins

We report (a) on the synthesis of a long-wavelength fluorescent coumarin containing an allyloxy acetate moiety, (b) the synthesis of two linkers containing an allyloxy acetate and an alkyne or azide function, respectively, and (c) the selective modification human serum albumin by a sequential method involving Pd(II) catalyzed modification of the phenolic side chain of tyrosine residues with an alkyne bearing linker and a subsequent azide–alkyne click reaction with an azide functionalized long-wavelength emitting coumarin dye. The method is likely to be applicable to various kinds of azido-modified fluorophores, and the Pd(II)-catalyzed modification of the tyrosines may also be used to introduce other kinds of tags. With these reagents, tyrosine specific modulation of proteins and peptides becomes possible either directly or in a sequential manner.     

Retrospective analysis of sequential dose-finding designs

The continual reassessment method (CRM) is a dose-finding design using a dynamic sequential updating scheme. In common with other dynamic schemes the method estimates a current dose level corresponding to some target percentile for experimentation. The estimate is based on all included subjects. This continual reevaluation is made possible by the use of a simple model. As it stands, neither the CRM, nor any of the other dynamic schemes, allow for the correct estimation of some target percentile, based on retrospective data apart from the exceptional situation in which the simplified model exactly generates the observations. In this article we focus on the very specific issue of retrospective analysis of data generated by some arbitrary mechanism and subsequently analyzed via the continual reassessment method. We show how this can be done consistently. The proposed methodology is not restricted to that particular design and is applicable to any sequential updating scheme in which dose levels are associated with percentiles via model inversion.     

On fixed precision level sequential sampling

Summary It is proposed that the sequential sampling design ofKuno (1969) for estimating populations with a fixed level of precision be modified by using σ²=am ^b for the variance-mean relationship for most field distributions of organisms. This function yields a straight line “stop line” rather than a curve. An example is calculated and used with field data.